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This phase I/II trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.

Best overall response rate (PR + CR) (Phase II) [ Time Frame: The time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented, assessed up to 12 weeks ]

MTD defined as the dose of carfilzomib added to standard R-ICE chemotherapy which, if exceeded, would put the patient at an undesirable risk of medically unacceptable dose-limiting toxicities (Phase I) [ Time Frame: 28 days ]

Secondary Outcome Measures:

Complete response rate according to the International Working Group Response criteria as reported by the revised Cheson criteria [ Time Frame: Up to 5 years ]

Efficacy rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.

Overall survival [ Time Frame: From the start of treatment until death for any reason, assessed up to 5 years ]

The estimated distributions of overall survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

Pharmacokinetics (PK)/pharmacodynamics (PD) of carfilzomib and standard R-ICE combination therapy in adult patients with relapsed/refractory diffuse large B-cell lymphoma [ Time Frame: Pre-dose, just prior to the end of the infusion; and at 15 minutes, 30 minutes, 1, 2, 4, 6 hours post infusion on course 1, day 1, then at 24 hours post course 1 infusion on course 1, day 2 (prior to day 2 infusion) ]

A population PK/PD structural model will be developed for carfilzomib based on degree of proteasome inhibition in relation to efficacy and toxicity endpoints in the proposed study using NONMEM. This model will describe the potential relationship between carfilzomib exposure in relation to proteasome inhibition to the time course of thrombocytopenia and neutropenia as indicators of pharmacodynamics response.

Progression-free survival [ Time Frame: Up to 5 years ]

The estimated distributions of progression-free survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

Toxicity of the addition of carfilzomib to R-ICE at the MTD, assessed by the CTEP version 4.0 of the NCI CTCAE [ Time Frame: Up to 5 years ]

Toxicity rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.

Other Outcome Measures:

Degree of proteasome inhibition determined by enzymatic assay for chymotrypsin-like activity [ Time Frame: Days 1-3 of course 1 ]

Patients receive carfilzomib IV over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

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*Note: If patient has cytopenias due to bone marrow involvement, these requirements are not applicable

Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL creatinine clearance must be > 60 mL/min within 7 days prior to treatment either measured or calculated using a standard Cockcroft and Gault formula

Written informed consent in accordance with federal, local, and institutional guidelines

Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

If HBV DNA is negative, the subject may be included but must undergo at least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the treatment course

Exclusion Criteria:

Patients with non-Hodgkin lymphoma (NHL) other than DLBCL; including "transformed" DLBCL

Known to be seropositive for human immunodeficiency virus (HIV); an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk

Positive serology for HBV defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test will be performed and if positive the subject will be excluded

Patients with symptomatic brain involvement

Peripheral neuropathy of grade 2 or greater severity as defined by the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; patients with grade 2 or higher (NCI-Common Toxicity Criteria [CTC]) neuropathy

Uncontrolled intercurrent illness including, but not limited to, active infection, poorly controlled hypertension, diabetes mellitus or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study

Pregnant or breastfeeding

Patient has received other investigational drugs within 4 weeks before enrollment

Chemotherapy within 3 weeks of the first scheduled study treatment

Less than 2-years disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate-specific antigen [PSA] levels); patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2 years have lapsed

Major surgery, other than diagnostic surgery, within 2 weeks

Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)

Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent)

Prior high-dose chemotherapy (HDC)-ASCT

Active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating DLBCL at the time of registration to this study is not exclusion for study enrollment

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01959698